An intriguingbut far from provenHIV cure in the ‘So Paulo Patient’ – Science Magazine
HIV, shown here budding from cell, remains stubbornly resistant to cure strategies because its DNA can lie silently in host chromosomes for years.
By Jon CohenJul. 7, 2020 , 9:00 AM
A 36-year-old man in Brazil has seemingly cleared an HIV infectionmaking him the proof of principle in humans of a novel drug strategy designed to flush the AIDS virus out of all of its reservoirs in the body. After receiving an especially aggressive combination of antiretroviral (ARV) drugs and nicotinamide (vitamin B3), the man, who asks to be referred to as the So Paulo Patient to protect his privacy, went off all HIV treatment in March 2019 and has not had the virus return to his blood.
The patients story is remarkable, says Steven Deeks, an HIV/AIDS clinician at the University of California, San Franciscowho was not involved with this study. But he and others, including the study leaders, caution that the success hasnt been long or definitive enough to label it a cure. Interesting anecdotes have long driven the HIV cure field, and they should be considered largely as hypothesis-generating observations that can simulate new areas of investigation, says Deeks, who also conducts HIV cure research.
Most people who suppress HIV with ARVs and later stop treatment see it come racing back to high levels within weeks. Not only did the So Paulo Patient not experience a rebound, but his HIV antibodies also dropped to extremely low levels, hinting at the possibility he may have cleared infected cells in the lymph nodes and gut.
Ricardo Diaz of the Federal University of So Paulo, the clinical investigator running the study, says he doesnt know whether the patient is cured. He has very little antigen, Diaz says, referring to HIV proteins that trigger the production of antibodies and other immune responses. But he notes his team has not sampled the mans lymph nodes or gut for the virus since he stopped treatment. Diaz discussed the patient today at a press conference for AIDS 2020, the 23rd International AIDS Conference taking place virtually this week, and he plans to present the study in full tomorrow.
Only two people are known to have been cured of their HIV infections:Timothy Ray Brown and a man who has asked to be referred to as the London Patient; both received bone marrow transplants as part of a treatment for cancers. The transplants cleared their infections and gave them new immune systems that resist infection with the virus. But bone marrow transplants are expensive, complicated interventions that can have serious side effects, making them an impractical cure for the 38 million people now living with the AIDS virus.
Other potential HIV cure cases have received intense media attention only to see the virus return after prolonged absences. Most soberingly, a baby in Mississippi who started ARVs shortly after birth stopped treatment at 18 months and was thought to be cured until the virus suddenly resurfaced more than 2 years later. Several adults who had bone marrow transplants and appeared to have been cured were not.
HIV has proven particularly difficult to eliminate because the virus weaves its genetic material into human chromosomes, where it can lie dormant, escaping the immune surveillance that typically eliminates foreign invaders. These silently infected cells may persist, perhaps indefinitely, because they have stem cell-like properties and can make clones of themselves. Researchers have come up with several strategies to flush reservoirs of cells that harbor latent HIV infections, but none have provedeffective.
To compare different reservoir-clearing strategies, Diaz and colleagues in 2015 recruited the So Paulo Patient and other individuals who had controlled their HIV infections with ARVs. The most aggressive approach, used in this man and four others, added two ARVs to the three they were already taking, in the hopethis would rout out any HIV that might have dodged the standard treatment. On top of this intensification, the study group received nicotinamide, which can, in theory, prod infected cells to wake up the latent virus. When those cells make new HIV, they either self-destruct or are vulnerable to immune attack.
After 48 weeks on this intensified schedule, the five trial participants returned to their regular three-drug regimen for 3 years, after which they stopped all treatment. Four saw the virus quickly return, but the So Paulo Patient has now gone 66 weeks without signs of being infected. Sensitive tests that detect viral genetic material did not find HIV in his blood. An even more sensitive test, which mixed his blood with cells that are susceptible to HIV infection, produced no newly infected cells.
Intriguingly, during the intensification period with nicotinamide, this man was the only one of the five who twice had the virus detected on standard blood tests. To Diaz, this suggests that latently infected cells had been roused, leading to blips of viral production. Im always trying to be a little bit the devils advocate, but in this case, Im optimistic, Diaz says. Maybe this strategy is not good for everybody because it only worked in one out of five here. But maybe it did get rid of virus. I dont know. I think this is a possibility.
Deeks says he does not know of any report, other than the two people cured by bone marrow transplants, of decreases in HIV antibody levels after stopping treatment. One large, outstanding question, he says, is whether the man indeed stopped taking his ARVs. I have not taken any HIV medication since March 30, 2019, the So Paulo Patient says. Diaz plans to confirm this by examining the mans blood for ARVs.
Another unknown is how soon the man started ARVs after becoming infected with HIV. Studies have shown that a small percentage of people who begin ARV treatment shortly after becoming infected have a better chance of controlling the virus for prolonged periods if they cease the drugs, presumably because they never built large reservoirs of infected cells. The So Paulo Patient started treatment 2 months after being diagnosed in October 2012. As with most people who become infected with HIV, he cannot say for certain when transmission occurred, but he suspects it was in June 2012. The only certainty is that he tested negative in 2010.
Its also unclear how nicotinamide would awaken silent infected cells. HIV DNA remains latent when it tightly spools around chromosome proteins known as histones. To make viral copies, it must unspool, and Diaz points to evidence that nicotinamide can trigger this unspooling in different ways.
Sharon Lewin, an HIV cure researcher who directs the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia, finds the antibody response intriguing. But she underscores it is not a convincing, controlled experiment. We need to move beyond case reports of HIV remission, Lewin says. I would be super excited to see long term remission in multiple participants in a clinical trial. This is what the field needs to really advance.
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An intriguingbut far from provenHIV cure in the 'So Paulo Patient' - Science Magazine